Pyridine or pyrimidine derivatives

Patent metadata

Field	Value
Publication number	US-10155741-B2
Application number	US-201815954964-A
Country	US
Kind code	B2
Filing date	Apr 17, 2018
Priority date	Oct 28, 2015
Publication date	Dec 18, 2018
Grant date	Dec 18, 2018

Abstract

The present invention relates to compounds of formula I

wherein
R 1′ is methyl; R 1 is methyl, ethyl, CF 3 , CH 2 OH, cyclopropyl or cyano, or R 1′ and R 1 may form together a 1,1-dioxo-tetrahydro-thiophen-3-yl ring; R 2 is hydrogen, methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, cyclopropylmethyl, or hydroxmethyl; R 3 is Cl, F, CF 3 , methyl, methoxy, or cyclopropyl; R 4 is hydrogen, methyl, F or Cl; X is N or CH; Y is N or CH;
with the proviso that X and Y are not simultaneously CH;

or to a pharmaceutically acceptable salt or acid addition salt, to a racemic mixture, or to its corresponding enantiomer and/or optical isomer and/or stereoisomer.

The compounds of formula I may be used in the treatment of psychiatric disorders such as schizophrenia, bipolar disorder, obsessive-compulsive disorder or autism spectrum disorder.

First claim

The invention claimed is:

1. A compound of formula I:

wherein
R 1′ is methyl;
R 1 is methyl, ethyl, CF 3 , CH 2 OH, cyclopropyl or cyano, or R 1′ and R 1 may form together a 1,1-dioxo-tetrahydro-thiophen-3-yl ring;
R 2 is hydrogen, methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, cyclopropylmethyl, or hydroxmethyl;
R 3 is Cl, F, CF 3 , methyl, methoxy, or cyclopropyl;
R 4 is hydrogen, methyl, F or Cl;
X is N or CH;
Y is N or CH;
with the proviso that X and Y are not simultaneously CH;

or a pharmaceutically acceptable salt or acid addition salt, a racemic mixture, or its corresponding enantiomer and/or optical isomer and/or stereoisomer.

2. A compound of formula IA according to claim 1 :

wherein
R 1″ is methyl;
R 1 is methyl, ethyl, CF 3 , CH 2 OH, cyclopropyl or cyano, or R 1′ and R 1 may form together a 1,1-dioxo-tetrahydro-thiophen-3-yl ring;
R 2 is hydrogen, methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, cyclopropylmethyl, or hydroxmethyl;
R 3 is Cl, F, CF 3 , methyl, methoxy, or cyclopropyl;
R 4 is hydrogen, methyl, F or Cl;
or a pharmaceutically acceptable salt or acid addition salt, a racemic mixture, or its corresponding enantiomer and/or optical isomer and/or stereoisomer.

3. A compound of formula IA according to claim 2 , or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of
N-tert-Butyl-2-(4-chlorophenyl)-6-(4-propan-2-yl-pyrimidin-5-yl)-pyridine-4-carboxamide;
N-tert-Butyl-2-(4-fluorophenyl)-6-(4-propan-2-yl-pyrimidin-5-yl)-pyridine-4-carboxamide;
N-tert-Butyl-2-(4-propan-2-yl-pyrimidin-5-yl)-6-[4-(trifluoromethyl)-phenyl]-pyridine-4-carboxamide;
N-tert-Butyl-2-(4-methylphenyl)-6-(4-propan-2-yl-pyrimidin-5-yl)-pyridine-4-carboxamide;
N-tert-Butyl-2-(3,4-difluorophenyl)-6-(4-propan-2-yl-pyrimidin-5-yl)-pyridine-4-carboxamide;
N-tert-Butyl-2-(4-fluoro-3-methylphenyl)-6-(4-propan-2-yl-pyrimidin-5-yl)-pyridine-4-carboxamide;
N-tert-Butyl-2-(4-chloro-3-fluorophenyl)-6-(4-propan-2-yl-pyrimidin-5-yl)-pyridine-4-carboxamide;
N-tert-Butyl-2-(4-cyclopropyl-phenyl)-6-(4-propan-2-yl-pyrimidin-5-yl)-pyridine-4-carboxamide;
2-(4-Chlorophenyl)-N-(2-cyclopropyl-propan-2-yl)-6-(4-propan-2-yl-pyrimidin-5-yl)-pyridine-4-carboxamide;
2-(4-Chlorophenyl)-N-(2-cyanopropan-2-yl)-6-(4-propan-2-yl-pyrimidin-5-yl)-pyridine-4-carboxamide;
2-(4-Chlorophenyl)-N-(1-hydroxy-2-methylpropan-2-yl)-6-(4-propan-2-yl-pyrimidin-5-yl)-pyridine-4-carboxamide;
2-(4-Chlorophenyl)-6-(4-propan-2-yl-pyrimidin-5-yl)-N-(1,1,1-trifluoro-2-methylpropan-2-yl)-pyridine-4-carboxamide;
N-tert-Butyl-2-(4-methoxyphenyl)-6-(4-propan-2-yl-pyrimidin-5-yl)-pyridine-4-carboxamide;
N-tert-Butyl-2-(3-fluoro-4-methylphenyl)-6-(4-propan-2-yl-pyrimidin-5-yl)-pyridine-4-carboxamide;
(RS)-2-(4-Fluorophenyl)-N-(3-methyl-1,1-dioxothiolan-3-yl)-6-(4-propan-2-yl-pyrimidin-5-yl)-pyridine-4-carb oxamide;
2-(4-Fluorophenyl)-N-(2-methylbutan-2-yl)-6-(4-propan-2-yl-pyrimidin-5-yl)-pyridine-4-carboxamide;
N-tert-Butyl-2-(4-ethyl-pyrimidin-5-yl)-6-(4-fluorophenyl)-pyridine-4-carboxamide;
N-tert-Butyl-2-(4-fluorophenyl)-6-(4-methylpyrimidin-5-yl)-pyridine-4-carboxamide;
N-tert-Butyl-2-(4-cyclopropylpyrimidin-5-yl)-6-(4-fluorophenyl)-pyridine-4-carboxamide;
N-tert-Butyl-2-(4-tert-butyl-pyrimidin-5-yl)-6-(4-fluorophenyl)-pyridine-4-carboxamide;
N-tert-Butyl-2-(4-tert-butylpyrimidin-5-yl)-6-(4-chlorophenyl)-pyridine-4-carboxamide; and
N-tert-Butyl-2-(4-tert-butyl-pyrimidin-5-yl)-6-[4-(trifluoromethyl)-phenyl]-pyridine-4-carboxamide.

4. A compound of formula IB according to claim 1 :

wherein
R 1′ is methyl;
R 1 is methyl, ethyl, CF 3 , CH 2 OH, cyclopropyl or cyano, or R 1′ and R 1 may form together a 1,1-dioxo-tetrahydro-thiophen-3-yl ring;
R 2 is hydrogen, methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, cyclopropylmethyl, or hydroxmethyl;
R 3 is Cl, F, CF 3 , methyl, methoxy, or cyclopropyl;
R 4 is hydrogen, methyl, F or Cl;
or a pharmaceutically acceptable salt or acid addition salt, a racemic mixture, or its corresponding enantiomer and/or optical isomer and/or stereoisomer.

5. A compound of formula IB according to claim 4 , or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of
N-tert-Butyl-2-(4-fluorophenyl)-6-(4-methylpyridin-3-yl)-pyridine-4-carboxamide;
N-tert-Butyl-2-(4-chlorophenyl)-6-(4-methylpyridin-3-yl)-pyridine-4-carboxamide;
N-tert-Butyl-2-(4-propan-2-yl-pyridin-3-yl)-6-[4-(trifluoromethyl)-phenyl]-pyridine-4-carboxamide;
N-tert-Butyl-2-(4-chlorophenyl)-6-(4-propan-2-yl-pyridin-3-yl)-pyridine-4-carboxamide; and
N-tert-Butyl-2-(4-fluorophenyl)-6-(4-propan-2-yl-pyridin-3-yl)-pyridine-4-carboxamide.

6. A process for the manufacture of a compound of formula I, or a pharmaceutically acceptable salt thereof, as defined in claim 1 , which process comprises:
a) reacting a compound of formula

with a compound of formula

to form a compound of formula I

or
b) reacting a compound of formula

with a compound of formula

to form a compound of formula I

7. A pharmaceutical composition comprising a compound of formula I as claimed in claim 1 , or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

8. A method for the treatment of schizophrenia, bipolar disorder, obsessive-compulsive disorder or autism spectrum disorder in a mammal, which method comprises administering an effective amount of a compound of formula I as claimed in claim 1 , or a pharmaceutically acceptable salt thereof, to the mammal.

Assignees

• Hoffmann La Roche

Inventors

• Hoener Marius
• Wichmann Juergen

Classifications

• C07D211/80

  having two double bonds between ring members or between ring members and non-ring members · CPC title

• A61P25/18

  Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia · CPC title

• C07D401/04 Primary

  directly linked by a ring-member-to-ring-member bond · CPC title

• A61K31/506

  not condensed and containing further heterocyclic rings · CPC title

• C07D401/14

  containing three or more hetero rings · CPC title